CN1053184C - Novel aconitine-like compound and antipyretic analgesic anti-inflammatory agent - Google Patents
Novel aconitine-like compound and antipyretic analgesic anti-inflammatory agent Download PDFInfo
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- CN1053184C CN1053184C CN95190076A CN95190076A CN1053184C CN 1053184 C CN1053184 C CN 1053184C CN 95190076 A CN95190076 A CN 95190076A CN 95190076 A CN95190076 A CN 95190076A CN 1053184 C CN1053184 C CN 1053184C
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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Abstract
A novel aconitine-like compound and an antipyretic analgesic anti-inflammatory agent containing the same as the active ingredient. The compound is highly safe, exhibits a potent analgesic activity, and has also antipyretic and anti-inflammatory activities. It can be used by itself for treating algetic, febrile and anti-inflammatory diseases. When used in combination with morphine, it can potentiate the analgesic effect of morphine, so that it can contribute to a reduction in the dose of morphine and the relief of the side effects thereof.
Description
Technical field
The invention relates to new compound and contain analgesic, analgesia, the anti-inflammatory agent of this compound as effective constituent with aconitine type chemical constitution.More particularly, the invention relates to by general formula (I) represented compound with aconitine type chemical constitution and salt thereof
In the formula,
R
1Be hydrogen atom or hydroxyl,
R
2Be acetoxyl group,
R
3Be the alkyl of 1-4 carbon atom,
R
4Be
(1) hydrogen atom, or
(2) hydroxyl, or
(3) acetoxyl group; In addition, the invention still further relates to a kind of analgesic, analgesia, anti-inflammatory agent, it is characterized in that containing by the represented compound of general formula (I) and salt thereof as effective constituent with aconitine type chemical constitution
In the formula,
R
1Be hydrogen atom or hydroxyl,
R
2Be acetoxyl group,
R
3Be the alkyl of 1-4 carbon atom,
R
4Be
(1) hydrogen atom, or
(2) hydroxyl, or
(3) acetoxyl group;
Background technology
The aconitine-type alkaloids that is contained in the piece root of China's aconitum plant has very strong analgesic activity and anti-inflammatory effect, and this is existing report (for example, TohokuJ.exp.Med., 128,175-187 (1979)) in the literature.But aconitine-type alkaloids material toxicity is very strong, thereby the safe handling scope is narrow.
The explanation of invention
In order to obtain both to keep aconitine-type alkaloids analgesia that material has, anti-inflammatory effect, and the new aconitine-type alkaloids derivative that toxicity is low again, the inventor has carried out various researchs, succeeded in developing " new aconitine compound and analgesia; anti-inflammatory agent " before this and (opened clear 63-211268 referring to the spy, the spy opens clear 63-211269, the spy opens clear 64-34956, Te Kaiping 1-143859 and spy open flat 3-223255), find again subsequently, the compound that connects on 14 carbon atoms of aconitine type chemical constitution chlorobenzoyl oxygen base has better activity, contains 14-O-to the analgesia as effective constituent of chlorobenzoyl aconine or its salt thereby successfully work out, anti-inflammatory agent (opening flat 5-17448) referring to the spy.Carried out research repeatedly on this basis again, found that: on 14 carbon atoms of aconitine type chemical constitution, connect in the compound to chlorobenzoyl oxygen base, the compound pharmacological effect that connects acetoxyl group on 15 carbon atoms is good especially, and security is very high.
Be used for pressure stimulus method and hot plate method as the analgesic activities evaluation method, be suitable for estimating the activity that morphine etc. has the compound of powerful pain-stopping effect, the non-steroidal type is analgesic, the analgesic activity of anodyne acetylsalicylic acid, indomethacin than morphine a little less than, with pressing stimulus method and hot plate method can't confirm that it is active significantly.In addition, when adopting hot plate method, the mouse that is caused by thermal stimulus licks sufficient action the neural participation of high-level center, thereby, when the assessing compound analgesic activity, compare the analgesic activity that more can reflect with other experimental technique to the people.Compound of the present invention adopts subcutaneous administration, when pressing stimulus method and hot plate method experiment, has confirmed to have the analgesic activity stronger to the chlorobenzoyl aconine than 14-O-, and confirmed to have refrigeration function for the rat of yeast pyrogenicity.In addition, during with compound subcutaneous administration of the present invention with the morphine intravenously administrable and simultaneously also with these two kinds of compounds, find that compound of the present invention can strengthen the analgesic activity of morphine consumingly.
Therefore compound of the present invention has very big contribution for painful diseases and fever, the diseases associated with inflammation that treatment has an intense pain.In addition, compound of the present invention, even also can not be suppressed with its analgesic activity with morphine antagonist yet, tool thinks that its mechanism of action is different with morphine, compound of the present invention and morphine are also used alleviating pain really, in addition, by reducing the consumption of morphine gradually, can alleviate continuous use morphine and the side effect that produces.The present invention finishes with regard to being based on above-mentioned cognition.
The invention provides the new compound that has by aconitine type chemical constitution shown in the above-mentioned general formula (I), also provide in addition to contain to have by the compound or its salt of aconitine type chemical constitution shown in the above-mentioned general formula (I) analgesic, analgesia, anti-inflammatory agent as effective constituent.
Explain the present invention below
Of the present invention is as initial substance by compound described below by the represented new compound of above-mentioned general formula (I), be replaced as that various other substituting groups manufacture, the napelline that described compound is represented by following (II) formula by being connected substituting group on its 3 or 15 or 14 or the nitrogen-atoms, mesaconitine, jesaconitine, hypaconitine, the 14-O-benzoyl aconine, 14-O-benzoyl mesaconitine, 14-O-methoxybenzoyl aconine, 14-O-benzoyl sea handkerchief aconine and pyrroles's napelline of representing by following (III), pyrroles's mesaconitine, pyrroles's jesaconitine, pyrroles's hypaconitine, 16-table pyrroles napelline, 16-table pyrroles mesaconitine, 16-table pyrroles jesaconitine, 16-table pyrroles hypaconitines etc. are known to have the compound of aconitine type chemical constitution and 15 carbonyl reduction of the compound that will be represented by following (III) formula, make 15 compounds that form hydroxyl.
Compound name R
1R
2R
3R
4Aconitine OH OAc H Et mesaconitine OH OAc H Me jesaconitine OH OAc OMe Et hypaconitine H OAc H Me14-O-benzoyl OH OH H Et aconine 14-O-benzoyl OH OH H Me mesaconitine 14-O-anisoyl-OH OH OMe Et aconine 14-O-benzoyl H OH H Me sea handkerchief aconine Ac:CH3CO, Me:CH
3, Et:CH
3CH
2 
Compound name R
1R
2R
3*
Pyrroles's napelline OH H Et β
Pyrroles's mesaconitine OH H Me β
Pyrroles's jesaconitine OH OMe Et β
Pyrroles's hypaconitine H H Me β
16-table pyrroles OH H Et α
Napelline
16-table pyrroles OH H Me α
Mesaconitine
16-table pyrroles OH OMe Et α
Jesaconitine
16-table pyrroles H H Me α
Hypaconitine
Me:CH
3, Et:CH
3CH
2, *: 16
OCH
3Coordination
For with acylated hydroxy, can appropriate solvent (for example pyridine) in, corresponding compounds and acyl chlorides that uses when making hydroxy esterification usually or acid anhydrides etc. are reacted.In above-mentioned material originally; selecting for use to exist on 3 and 15 in the structural formula on the hydroxyl, 8 does not exist the compound of ethanoyl as initial substance; with diacetyl oxide during as acetylizing agent; acetylization reaction preferably carries out on 15, and can obtain with the 15-O-acetyl compounds is the resultant of principal product.
Be replaced as other substituting group in order to be connected alkyl substituent on the nitrogen-atoms, at first, make corresponding compounds in appropriate solvent (for example acetone) with the reaction of suitable oxygenant (for example potassium permanganate), form N-and remove the alkyl body, make resulting N-go alkyl body and the alkylating agent (for example alkylogen) that is used to introduce desirable alkyl to react then.
The reduction reaction of carbonyl can be undertaken by the following stated, is about to corresponding compounds and is dissolved in the appropriate solvent (for example ethanol or acetate), makes catalyzer, shortening under room temperature or heating condition with platinum oxide, palladium charcoal or Raney nickel etc.In addition, the reduction reaction of carbonyl also can be undertaken by the following stated, being about to corresponding compounds is dissolved in the appropriate solvent (for example ether), add metal hydride ligand (for example lithium aluminum hydride, sodium borohydride, hydrogenation tert.-butoxy aluminium lithium or hydrogenation aluminum methylate lithium etc.), under suitable temperature, stir.
The represented compound of above-mentioned in order to obtain (I) formula can carry out myriad combinations with above-mentioned each reaction.
Compound of the present invention can also form various salt with organic acids such as mineral acids such as hydrochloric acid, sulfuric acid, Hydrogen bromide or oxalic acid, succsinic acid, tartrate, citric acid, xitix.
The following describes the compound manufacturing embodiment that represents by (I) formula of the present invention.After the narration of embodiment, provide the analytical data of resulting compound among each embodiment.The pharmacological action relevant, toxicity and other have been recorded and narrated among the table 7-13 below with compound.In addition, the compound number in the following table and the contrast of compound title are listed in the table 1.
Embodiment 1
The 500mg napelline is dissolved in 5% potassium hydroxide/methanol solution of 5ml, at room temperature stirred 10 hours.The methyl alcohol in the dereaction liquid is heated up in a steamer in decompression, in residue, add the 5ml frozen water then, add to its dissolving, with it and filled the macroreticular-type resin Amberlite XAD-2 that 100ml washs successively with methyl alcohol, water in advance (Japanese Ao Erjianuo company), wash with water.After confirming that washing lotion no longer shows alkalescence, use the 1000ml methanol-eluted fractions, under reduced pressure concentrate in solid elutriant, obtain the residue that 480mg contains aconine, this residue is dissolved in the distilled in advance pyridine of 10ml, add the 0.3ml parachlorobenzoyl chloride, stirred 10 minutes down at-18 ℃, after reaction finishes, reaction solution is added in the silica gel column chromatography (50g), use the 150ml chloroform successively, 150ml 5% methyl alcohol/chloroform, 150ml 10% methyl alcohol/chloroform, 150ml 15% methyl alcohol/chloroform and 20% methyl alcohol/chloroform wash-out merges 10% methyl alcohol/chloroform elutriant and 15% methyl alcohol/chloroform elutriant, under reduced pressure concentrates and does admittedly.With silica gel column chromatography (150g) this residue (parting liquid: the saturated chloroform of ammonia), with acetone/hexane recrystallize, obtain 400mg 14-O-that separates, purifies to the chlorobenzoyl aconine.
Embodiment 2
Add 10ml diacetyl oxide and 5ml pyridine at the 300mg 14-O-that obtains of operation similarly to Example 1 in to the chlorobenzoyl aconine, at room temperature stirred 1 hour.Reaction solution is injected frozen water, make it to become alkalescence, use this reaction solution of 100ml extracted with diethyl ether 3 times then, wash ether extraction liquid with water, after the saltcake drying, under reduced pressure concentrate and do admittedly with 10% ammoniacal liquor.With silica gel thin-layer chromatography (parting liquid: chloroform/ether=1: 1, ammonia saturated with vapor) separation, purification residue, obtain 15-O-ethanoyl-14-O-to chlorobenzoyl aconine 145mg.
Embodiment 3
208mg 15-O-ethanoyl-14-O-is dissolved in the 25ml acetone the chlorobenzoyl aconine, adds that in this solution 127mg potassium permanganate is dissolved in solution 25ml in the 25ml acetone mixed solution (1: 1), at room temperature stirred 1.5 hours.After reaction finishes, in ice-cooled downhill reaction liquid, add 2N sulfuric acid and make it to become acidity, add S-WAT and become transparent until the color of reaction solution.Concentration of reaction solution under reduced pressure makes this concentrated solution become alkalescence with 10% ammoniacal liquor then, with 100ml chloroform extraction 3 times, washing chloroform layer, after the saltcake drying, under reduced pressure concentrate do solid.With silica gel column chromatography (10g, the saturated chloroform of 5% methyl alcohol/ammonia) separate, the purification residue, obtaining 93.4mg takes off-N-ethyl-15-O-ethanoyl-14-O-is to the chlorobenzoyl aconine.
Embodiment 4
With the napelline among the 500mg mesaconitine replacement embodiment 1, in addition operation similarly to Example 1 obtains 398mg 14-O-to the chlorobenzoyl mesaconitine.
Embodiment 5
Add 3.5ml diacetyl oxide and 2ml pyridine at 100mg 14-O-in to the chlorobenzoyl mesaconitine, at room temperature stirred 1 hour.After the reaction end, in reaction solution impouring frozen water, make it to become alkalescence, use 50ml extracted with diethyl ether 3 times, wash ether extraction liquid with water, after the saltcake drying, under reduced pressure concentrate and do admittedly with 10% ammoniacal liquor.With silica gel thin-layer chromatography (parting liquid: chloroform/ether=1: 1, ammonia saturated with vapor) separation, purification residue, obtain 50.3mg 15-O-ethanoyl-14-O-to the chlorobenzoyl mesaconitine.
Embodiment 6
The 50mg that obtains of operation is similarly to Example 3 taken off-N-ethyl-15-O-ethanoyl-14-O-is dissolved in the 2ml methanol mixed solution (1: 1) the chlorobenzoyl aconine; add 65mg lime carbonate and 0.2ml propyl iodide; reflux 2 hours; after the cooling; reaction mixture is removed by filter insolubles, under reduced pressure concentrate and do solid reaction solution.With silica gel column chromatography (5g, the saturated chloroform of 5% methyl alcohol/ammonia) separate, the purification residue, obtaining 28mg takes off-N-ethyl-N-propyl group-15-O-ethanoyl-14-O-is to the chlorobenzoyl aconine.
Embodiment 7
(1) under decompression (1.5-2mmHg) and 200 ℃ with 100mg mesaconitine fusion 30 minutes, after the cooling, with silica gel column chromatography (10g, 5% methyl alcohol/chloroform) separate, the purified reaction mixture, obtain 56mg pyrroles's mesaconitine.
(2) 50mg pyrroles's mesaconitine is dissolved in the 5mg exsiccant tetrahydrofuran (THF), in addition, the 144mg lithium aluminium hydride is suspended in the 5ml tetrahydrofuran (THF), add 0.46ml methyl alcohol, at room temperature stir, obtain the tetrahydrofuran solution of hydrogenation trimethoxy lithium aluminium.Under-70 ℃ this solution of 5ml slowly is added drop-wise in the tetrahydrofuran solution of above-mentioned pyrroles's mesaconitine, stirring reaction liquid 1 hour under this temperature at room temperature stirred 1 hour more then.In ice-cooled downhill reaction liquid, slowly add the tetrahydrofuran solution that contains less water, remove by filter insolubles after, concentrating under reduced pressure is done solid filtrate.With silica gel column chromatography (15g, the saturated chloroform of 5% methyl alcohol/ammonia) separation, purification residue, obtain 46mg 8-deoxidation mesaconitine.
(3) 45mg 8-deoxidation mesaconitine is dissolved in the 0.5ml pyridine, in this solution, drips 0.5ml parachlorobenzoyl chloride/pyridine (0.05ml/0.5ml) solution, at room temperature stirred 2.5 hours.Reaction is injected frozen water with reaction solution after finishing, and makes it to become acidity with 10% hydrochloric acid, then with 50ml ether washing 2 times.After 10% ammoniacal liquor makes the hydrochloric acid layer become alkalescence, use 50ml extracted with diethyl ether 3 times, the washing ether layer after the saltcake drying, under reduced pressure concentrates and does admittedly.With aluminum oxide column chromatography (5g, chloroform) separation, purification residue, obtain 32mg 8-deoxidation-14-O-to the chlorobenzoyl mesaconitine.
Embodiment 8
(1) under decompression (1.5-2mmHg) and 200 ℃ with 100mg mesaconitine fusion 30 minutes, after the cooling, with silica gel column chromatography (10g, 5% methyl alcohol/chloroform) separate, the purified reaction mixture, obtain 60mg pyrroles's napelline.
(2) use 50mg pyrroles's napelline to replace pyrroles's mesaconitine of embodiment 7 (2), in addition, obtain 47mg 8-deoxidation aconine with embodiment 7 (2) same operation.
(3) use 45mg 8-deoxidation aconine to replace the 8-deoxidation mesaconitine of embodiment 7 (3), in addition, obtain 36mg 8-deoxidation-14-O-the chlorobenzoyl aconine with embodiment 7 (3) same operation.
Embodiment 9
50mg pyrroles's napelline is dissolved in 5ml 5% potassium hydroxide/methanol solution, at room temperature stirred 3 hours.After reaction finishes, under reduced pressure concentrate and do solid reaction solution, residue is dissolved in the 10ml water.This solution is added to filled 100ml macroreticular-type resin Amberlite XAD-2 (Japanese Ao Erjianuo company), wash with water until elutriant and no longer show alkalescence, use methanol-eluted fractions then, under reduced pressure concentrate and do solid this meoh eluate, with silica gel column chromatography (10g, the saturated chloroform of 10% methyl alcohol/ammonia) separation, purification residue obtain 43mg 16-table pyrroles aconine.
Embodiment 10
(1) operation similarly to Example 9 obtains 45mg 16-table pyrroles aconine.
(2) replace pyrroles's mesaconitine of embodiment 7 (2) with 40mg 16-table pyrroles aconine, in addition, obtain 36mg8-deoxidation-16-and show aconine with the same operation of embodiment 7 (2).
(3) replace the 8-deoxidation mesaconitine of embodiment 7 (3) with 36mg 8-deoxidation-16-table aconine, in addition, obtain 28.6mg 8-deoxidation-16-table-14-O-the chlorobenzoyl aconine with the same operation of embodiment 7 (3).
Embodiment 11
(1) with pyrroles's napelline of 50mg pyrroles's mesaconitine replacement embodiment 9, in addition operation similarly to Example 9 obtains 42mg 16-table pyrroles mesaconitine.
(2) replace pyrroles's mesaconitine of embodiment 7 (2) with 42mg 16-table pyrroles mesaconitine, in addition, obtain 37.6mg8-deoxidation-16-and show mesaconitine with the same operation of embodiment 7 (2).
(3) replace the 8-deoxidation mesaconitine of embodiment 7 (3) with 37mg 8-deoxidation-16-table mesaconitine, in addition, obtain 33mg 8-deoxidation-16-table-14-O-the chlorobenzoyl mesaconitine with the same operation of embodiment 7 (3).
Embodiment 12
Add 0.5ml diacetyl oxide and 1ml pyridine at 100mg 14-O-in to the chlorobenzoyl aconine, at room temperature stirred 12 hours.Reaction is injected frozen water with reaction solution after finishing, and makes it to become alkalescence with 10% ammoniacal liquor, uses the 50ml extracted with diethyl ether then 3 times, washes ether layer with water, after the saltcake drying, under reduced pressure concentrates dried solid.With silica gel thin-layer chromatography (parting liquid: chloroform/methanol=50: 1, ammonia saturated with vapor) separation, purification residue, obtain 74mg 3,15-two-O-ethanoyl-14-O-is to the chlorobenzoyl aconine.
Embodiment 13
The 14-O-that the chlorobenzoyl mesaconitine is replaced embodiment 12 with 65mg 14-O-is to the chlorobenzoyl aconine, and in addition operation similarly to Example 12 obtains 32mg 3, and 15-two-O-ethanoyl-14-O-is to the chlorobenzoyl mesaconitine.
Embodiment 14
(1) with the napelline among the 500mg hypaconitine replacement embodiment 1, in addition operation similarly to Example 1 obtains 380mg 14-O-to chlorobenzoyl sea handkerchief aconine.
(2) replace 14-O-among the embodiment 12 to the chlorobenzoyl aconine with 100mg 14-O-to chlorobenzoyl sea handkerchief aconine, in addition operation similarly to Example 12 obtains 53mg 15-O-ethanoyl-14-O-to chlorobenzoyl sea handkerchief aconine.
Embodiment 15
Replace 14-O-among the embodiment 5 to the chlorobenzoyl mesaconitine with 30mg 8-deoxidation-14-O-to the chlorobenzoyl mesaconitine, in addition operation similarly to Example 5 obtains 21mg 15-O-ethanoyl-8-deoxidation-14-O-to the chlorobenzoyl mesaconitine.
Embodiment 16
Replace 14-O-among the embodiment 5 to the chlorobenzoyl mesaconitine with 30mg 8-deoxidation-14-O-to the chlorobenzoyl aconine, in addition operation similarly to Example 5 obtains 22mg 15-O-ethanoyl-8-deoxidation-14-O-to the chlorobenzoyl aconine.
Embodiment 17
(1) operates equally with (1), (2), (3) of embodiment 10, obtain 30mg 8-deoxidation-16-table-14-O-the chlorobenzoyl aconine.
(2) with 30mg 8-deoxidation-16-table-14-O-to the 14-O-among the chlorobenzoyl aconine replacement embodiment 5 to the chlorobenzoyl mesaconitine; in addition operation similarly to Example 5 obtains 24mg 15-O-ethanoyl-8-deoxidation-16-table-14-O-to the chlorobenzoyl aconine.
Embodiment 18
Replace 15-O-ethanoyl-14-O-among the embodiment 3 to the chlorobenzoyl aconine with 24mg 15-O-ethanoyl-8-deoxidation-16-table-14-O-to the chlorobenzoyl aconine; operation similarly to Example 3 in addition, obtaining 12mg takes off-and N-ethyl-15-O-ethanoyl-8-deoxidation-16-table-14-O-is to the chlorobenzoyl aconine.
Embodiment 19
1. with embodiment 11 1., 2., 3. equally the operation, obtain 35mg 8-deoxidation-16-table-14-O-to the chlorobenzoyl mesaconitine.
2. with 35mg 8-deoxidation-16-table-14-O-to the 14-O-among the chlorobenzoyl mesaconitine replacement embodiment 5 to the chlorobenzoyl mesaconitine; in addition operation similarly to Example 5 obtains 27mg 15-O-ethanoyl-8-deoxidation-16-table-14-O-to the chlorobenzoyl mesaconitine.
Embodiment 20
With 50mg take off-N-ethyl-15-O-ethanoyl-8-deoxidation-16-table-14-O-replaces taking off among the embodiment 6-N-ethyl-15-O-ethanoyl-14-O-to the chlorobenzoyl aconine to the chlorobenzoyl aconine; in addition operation similarly to Example 6, obtaining 25mg takes off-and N-ethyl-N-propyl group-15-O-acyl group-8-deoxidation-16-table-14-O-is to the chlorobenzoyl aconine.
Table 1 compound number and compound title synopsis
Compound N o. compound name
(1) 15-O-ethanoyl-14-O-is to the chlorobenzoyl mesaconitine
(2) 15-O-ethanoyl-14-O-is to the chlorobenzoyl aconine
(3) take off-the N-ethyl-N-propyl group-15-O-acetyl
Base-14-O-is to the chlorobenzoyl aconine
(4) 3,15-two-O-ethanoyl-14-O-to chlorobenzoyl aconine (5) 3,15-two-O-acyl group-14-O-to the rhizome of Chinese monkshood in the chlorobenzoyl
Rather (6) 15-O-ethanoyl-14-O-to chlorobenzoyl sea handkerchief aconine (7) 15-O-ethanoyl-8-deoxidation-14-O-to crow in the chlorobenzoyl
Peaceful (8) 15-O-ethanoyl of head-8-deoxidation-14-O-is to the chlorobenzoyl rhizome of Chinese monkshood
Amine (9) 15-O-acyl group-8-deoxidation-16-table-14-O-is to chlorobenzene
Formyl mesaconitine (10) 15-O-ethanoyl-8-deoxidation-16-table-14-O-is to chlorine
Benzoyl aconine (11) takes off-and N-ethyl-N-propyl group-15-O-ethanoyl-8-takes off
Oxygen-16-table-14-O-is to chlorobenzoyl aconine table 2 1) infrared absorption spectrum analysis (IR) compound N o. IR (KBr, cm
-1), (1) 1715, (2) 1710, (3) 1715, (4) 1715, (5) 1715, (6) 1720, (7) 1710, (8) 1717, (9) 1717, (10) 1710, (11) 1715 tables 3 2) ultra-violet absorption spectrum analysis, (UV) compound N o.
Nm, (log ε), (1) 246, (3.97), (2) 246, (3.98), (3) 246, (3.98), (4) 246, (4.03), (5) 246, (4.01), (6) 246, (3.97), (7) 246, (4.00), (8) 246, (4.01), (9) 246, (3.97), (10) 246, (4.01), (11) 246, (3.98) table 4 3)
1H-nmr analysis compound N o. δ, ppm (CDCl
3) (1) 7.98 (2H, d, J=8.7Hz), 7.43 (2H, d,
J=8.7Hz) (to the H of chlorobenzene formacyl)
5.34 (1H, d, J=6.0Hz) (15 H)
4.92 (1H, d, J=5.1Hz) (14 H)
3.72(3H，s)，3.31(3H，s)，3.29
(3H, s), 3.26 (3H, s) (1,6,16,18
The H of methyl of methoxyl group), 2.35 (3H,
S) (H of the methyl of N-methyl)
2.22 (3H, s) (the H table 4 (continuing) 3 of the methyl of 15 ethanoyl)
1H-nmr analysis compound N o. δ, ppm (CDCl
3) (2) 7.98 (2H, d, J=8.7Hz), 7.42 (2H, d,
J=8.7Hz) (to the H of chlorobenzene formacyl)
5.33 (1H, d, J=6.0Hz) (15 H)
4.92 (1H, d, J=5.1Hz) (14 H)
3.72(3H，s)，3.31(3H，s)，3.30
(3H, s), 3.25 (3H, s) (1,6,16,18
The H of methyl of methoxyl group)
2.22 (3H, the s) (methyl of 15 ethanoyl
H), 1.14 (3H, t, J=7.2Hz) (N-
The H of the methyl of ethyl) (3) 7.99 (2H, d, J=8.7Hz), 7.42 (2H, d,
J=8.7Hz) (to the H of chlorobenzene formacyl)
5.32 (1H, d, J=6.3Hz) (15 H)
4.92 (1H, d, J=5.1Hz) (14 H)
3.71(3H，s)，3.30(3H，s)，3.29
(3H, s), 3.26 (3H, s) (1,6,16,18
The H of methyl of methoxyl group)
2.24 (3H, the s) (methyl of 15 ethanoyl
H), 0.93 (3H, t, J=7.0Hz) (N-
The H of the methyl of propyl group) table 4 (continuing) 3)
1H-nmr analysis compound N o. δ, ppm (CDCl
3) (4) 7.99 (2H, d, J=8.7Hz), 7.41 (2H, d,
J=8.7Hz) (to the H of chlorobenzene formacyl)
5.36 (1H, d, J=6.0Hz) (15 H)
4.92 (1H, d, J=5.1Hz) (14 H)
4.90 (1H, dd, J=10.4,5.3Hz) (3
H)，3.60(3H，s)，3.26(3H，s)，
3.24(3H，s)，3.21(3H，s)(1，6，16，
The H of the methyl of 18 methoxyl group)
2.21 (3H, s), 2.06 (3H, s) (ethanoyl
The H of methyl), 1.14 (3H, t, J=7.2
Hz) (H of the methyl of N-ethyl) (5) 7.99 (2H, d, J=8.7Hz), 7.42 (2H, d,
J=8.7Hz) (p-is to the H of chlorobenzene formacyl)
5.35 (1H, d, J=6.0Hz) (15 H)
4.91 (1H, d, J=5.1Hz) (14 H)
4.90 (1H, dd, J=10.5,5.2Hz) (3
H)，3.60(3H，s)，3.28(3H，s)，
3.25(3H，s)，3.21(3H，s)(1，6，16，
The H of the methyl of 18 methoxyl group)
2.33 (3H, s) (H of N-methyl)
2.22 (3H, s), 2.06 (3H, s) (ethanoyl
The H of methyl) table 4 (continuing) 3)
1H-nmr analysis compound N o. δ, ppm (CDCl
3) (6) 7.99 (2H, d, J=8.7Hz), 7.42 (2H, d,
J=8.7Hz) (p-is to the H of chlorobenzene formacyl)
5.35 (1H, d, J=6.0Hz) (15 H)
4.93 (1H, d, J=5.4Hz) (14 H)
3.60(3H，s)，3.30(3H，s)，3.29
(3H, s), 3.22 (3H, s) (1,6,16,18
The H of methyl of methoxyl group)
2.31 (3H, s) (H of N-methyl)
2.22 (3H, s) (H of the methyl of ethanoyl) (7) 7.97 (2H, d, J=8.8Hz), 7.43 (2H, d,
J=8.8Hz) (to the H of chlorobenzene formacyl)
4.85 (1H, d, J=5.0Hz) (14 H)
4.64 (1H, dd, J=12.0,6.0Hz) (15
H)，3.69(3H，s)，3.30(3H，s)，
3.28(3H，s)，3.25(3H，s)(1，6，16，
The H of the methyl of 18 methoxyl group)
2.35 (3H, s) (H of N-methyl)
2.22 (3H, s) (HH of the methyl of ethanoyl) (8) 7.97 (2H, d, J=8.8Hz), 7.43 (2H, d,
J=8.8Hz) (to the H of chlorobenzene formacyl)
4.86 (1H, d, J=5.0Hz) (14 H)
4.64 (1H, dd, J=12.0,6.0Hz) (15
H), 3.70 (3H, s), 3.31 (3H, s), table 4 (continuing) 3)
1H-nmr analysis compound N o. δ, ppm (CDCl
3)
3.28(3H，s)，3.25(3H，s)(1，6，16，
The H of the methyl of 18 methoxyl group)
2.23 (3H, s) (H of the methyl of ethanoyl)
1.11 (3H, t, J=7.0Hz) (the N-ethyl
The H of methyl) (9) 7.98 (2H, d, J=8.9Hz), 7.42 (2H, d,
J=8.9Hz) (to the H of chlorobenzene formacyl)
5.00 (1H, d, J=4.0Hz) (14 H)
4.73 (1H, t, J=12.0Hz) (15 H)
3.67(3H，s)，3.30(3H，s)，3.29
(3H, s), 3.25 (3H, s) (1,6,16,18
The H of methyl of methoxyl group)
2.35 (3H, s) (H of N-methyl)
2.24 (3H, s) (H of the methyl of ethanoyl) (10) 7.98 (2H, d, J=8.9Hz), 7.42 (2H, d,
J=8.9Hz) (to the H of chlorobenzene formacyl)
4.98 (1H, d, J=4.0Hz) (14 H)
4.74 (1H, t, J=12.0Hz) (15 H)
3.66(3H，s)，3.31(3H，s)，3.30(3H，
S), 3.26 (3H, s) (1,6,16,18
The H of methyl of methoxyl group), 2.25 (3H, s)
(H of the methyl of ethanoyl) 1.12 (3H, t
, J=7.0Hz) (H of the methyl of N-ethyl) table 4 (continuing) 3)
1H-nmr analysis compound N o. δ, ppm (CDCl
3)
(11) 7.98(2H，d，J＝8.9Hz)，7.42(2H，d，
J=8.9Hz) (to the H of chlorobenzene formacyl)
4.98 (1H, d, J=4.1Hz) (14 H)
4.75 (1H, t, J=11.8Hz) (15 H)
3.67(3H，s)，3.31(3H，s)，3.30
(3H, s), 3.26 (3H, s) (1,6,16,18
The H of methyl of methoxyl group)
2.25 (3H, s) (H of the methyl of ethanoyl)
0.98 (3H, t, J=7.0Hz) (the N-propyl group
The H of methyl) table 5 4)
13C-nmr analysis compound N o. δ, ppm (CDCl
3) (1) 173.4 (carbonyl of 15 ethanoyl
C), 165.4 (to chlorobenzene formacyl
The C of carbonyl), 139.5,131.1,128.8
, 128.4 (to the C of chlorobenzene formacyl),
88.5，87.7，82.3，81.9，79.3，76.5，
76.0，74.5，72.2(16，15，6，1，14，
18,8,13,3 C), 60.9,59.1,
57.6,56.0 (16 ', 18 ', 6 ', 1 ' C),
(42.3 the C of the methyl of N-methyl), 21.0
The C of the methyl of ethanoyl) table 5 (continuing) 4)
13C-nmr analysis compound N o. δ, ppm (CDCl
3) (2) 173.4 (carbonyls of 15 ethanoyl
C), 165.4 (to chlorobenzene formacyl
The C of carbonyl), 139.5,131.1,128.7
, 128.4 (to the C of chlorobenzene formacyl),
88.6，87.6，82.3，82.0，79.3，76.5，
76.1，74.6，72.3(16，15，6，1，14，
18,8,13,3 C), 60.9,59.1,
57.6,56.0 (16 ', 18 ', 6 ', 1 ' C),
(47.1 the C of the methylene radical of N-ethyl),
(20.9 the C of the methyl of ethanoyl), 13.4
(C of the methyl of N-ethyl) (3) 173.3 (carbonyls of 15 ethanoyl
C), 165.4 (to chlorobenzene formacyl
The C of carbonyl), 139.4,131.1,128.7
, 128.4 (to the C of chlorobenzene formacyl),
88.5，87.6，82.4，82.0，79.3，76.5，
76.1，74.5，72.3(16，15，6，1，14，
18,8,13,3 C), 60.9,59.1,
57.6,56.0 (16 ', 18 ', 6 ', 1 ' C),
(21.0 the C of the methyl of ethanoyl), 10.3
(C of the methyl of N-propyl group) table 5 (continuing) 4)
13C-nmr analysis compound N o. δ, ppm (CDCl
3) (4) 173.3,170.1 (carbonyl of ethanoyl
C), 165.3 (to chlorobenzene formacyl
The C of carbonyl), 139.3,131.1,128.7
, 128.4 (to the C of chlorobenzene formacyl),
88.7，87.5，82.8，81.9，79.3，76.5，
74.7，71.7，71.5(16，15，6，1，14，
8,13,18,3 C), 61.4,58.7,
57.8,56.2 (16 ', 18 ', 6 ', 1 ' C),
(47.4 the C of the methylene radical of N-ethyl),
21.1,20.9 (C of the methyl of ethanoyl),
(13.5 the C of the methyl of N-ethyl) (5) 173.3,170.1 (carbonyl of ethanoyl
C), 165.3 (to chlorobenzene formacyl
The C of carbonyl), 139.3,131.1,128.7
, 128.4 (to the C of chlorobenzene formacyl),
88.6，87.6，82.6，81.9，79.2，76.4，
74.7，71.7，71.3(16，15，6，1，14，
8,13,18,3 C), 61.3,58.7,
57.8,56.5 (16 ', 18 ', 6 ', 1 ' C),
(42.5 the C of the methyl of N-methyl), 21.1,
(21.0 the C of the methyl of ethanoyl) table 5 (continuing) 4)
13C-nmr analysis compound N o. δ, ppm (CDCl
3) (6) 173.4 (the carbonyl C of ethanoyl),
165.3 (to the carbonyl of chlorobenzene formacyl
C)，139.3，131.1，128.7，
(128.5 to the C of chlorobenzene formacyl),
88.6，87.6，85.0，82.3，80.3，79.3，
76.4，74.7(16，15，6，1，18，14，8，
13 C), 61.3,59.0,57.6,56.4
(16 ', 18 ', 6 ', 1 ' C), 42.7 (N-
The C of the methyl of methyl), 21.0 (ethanoyl
The C of methyl) (7) 173.3 (the carbonyl C of ethanoyl),
165.2 (to the carbonyl of chlorobenzene formacyl
C), 139.6,131.1,128.8,
(128.1 to the C of chlorobenzene formacyl),
92.0，85.0，83.6，80.9，80.7，77.3，
75.0，71.6(16，6，1，15，14，18，13
, 3 C), 61.7,59.1,57.8,56.0
(16 ', 18 ', 6 ', 1 ' C), 42.3 (N-
The C of methyl), 20.8 (ethanoyl
The C of methyl) (8) 173.2 (C of the carbonyl of ethanoyl),
165.0 (to the carbonyl of chlorobenzene formacyl
C), 139.7,131.1,128.9, table 5 (continuing) 4)
13The C-nmr analysis, compound N o. δ, ppm (CDCl
3)
(128.1 to the C of chlorobenzene formacyl),
92.1，85.0，83.6，80.8，80.7，77.3，
75.0，71.5(16，6，1，15，14，18，13
, 3 C), 61.7,59.0,57.8,56.0
(16 ', 18 ', 6 ', 1 ' C), 47.1 (N-
The C of the methylene radical of ethyl), 20.8 (
The C of the methyl of ethanoyl), 13.4 (the N-ethyl
The C of methyl) (9) 173.3 (C of the carbonyl of ethanoyl),
165.1 (to the carbonyl of chlorobenzene formacyl
C)，139.4，131.1，128.7，
(128.4 to the C of chlorobenzene formacyl),
88.9，85.0，82.4，80.8，79.9，77.5，
75.9，71.8(16，6，1，15，14，18，13
, 3 C), 62.2,59.1,58.0,56.2
(16 ', 18 ', 6 ', 1 ' C), 42.3 (N-
The C of methyl), 21.0 (ethanoyl
The C of methyl) (10) 173.3 (C of the carbonyl of ethanoyl),
165.1 (to the カ Le ボ of the carbonyl of chlorobenzene formacyl
C)，139.4，131.1，128.7，
(128.4 to the C of chlorobenzene formacyl),
88.9,85.1,82.6,80.7,79.8,77.4. table 5 (continuing) 4)
13C-nmr analysis compound N o. δ, ppm (CDCl
3)
76.0，71.8(16，6，1，15，14，18，13
, 3 C), 62.2,59.1,58.0,55.8
(16 ', 18 ', 6 ', 1 ' C), 47.4 (N-
The C of the methylene radical of ethyl), 21.0 (
The C of the methyl of ethanoyl), 13.4 (N-
The C of the methyl of ethyl) (11) 173.2 (C of the carbonyl of ethanoyl),
165.0 to the carbonyl of chlorobenzene formacyl
C)，139.4，131.1，128.7，
(128.4 to the C of chlorobenzene formacyl),
89.0，85.1，82.6，80.7，79.9，77.4，
75.9，71.8(16，6，1，15，14，18，13
, 3 C), 62.1,59.1,58.0,55.9
(16 ', 18 ', 6 ', 1 ' C), 21.0 (
The C of the methyl of ethanoyl), 10.3 (N-
The C of the methyl of propyl group) table 6 5) mass spectroscopy compound N o. M
+(m/z)
(1) 665，667
(2) 679，681
(3) 693，695
(4) 721，723
Table 6 (continuing) 5) mass spectroscopy
Compound N o. M
+(m/z)
(5) 707，709
(6) 649，651
(7) 649，651
(8) 663，665
(9) 649，651
(10) 663，665
(11) 677，679
The following describes the drug effect of the compound of representing by (I) formula of the present invention and the experimental example of acute toxicity.
Experimental example 1
(1) adopt the pressure stimulus method to measure analgesic activities
Circadian Std:ddY is that male mice (20-25g) experimentizes with stopping to take food.Compound shown in the table 1 is made tartrate, with 0.9% normal saline solution they are dissolved into the concentration of 10mg/10ml, as sample solution.Contrast adopts 0.9% normal saline solution.Experiment is adopted and is pressed stimulating apparatus to carry out.Before the sample solution administration, with twice pain threshold of 30 minutes measuring spaces, selecting pain threshold for use is that the mouse of 50-100mmHg is used for experiment.With the dosage subcutaneous administration of said sample solution, measure pain threshold with the pressure stimulating apparatus after 1 hour with 10ml/kg.Control group is with the dosage subcutaneous administration of 0.9% normal saline solution with 10ml/kg.Experimental result is represented with the inhibiting rate (%) shown in the following formula.For preventing the damage of mouse tail root tissue, be 230mmHg with the cutoff compression set.The results are shown in the following table 7.By shown in the table 7 as can be seen, compound of the present invention has the powerful pain-stopping activity, its action intensity than 14-O-to chlorobenzoyl aconine height.
Inhibiting rate (%)=(A-B) * 100/ (C-B)
A: the pain threshold after the sample solution administration (mmHg)
B: the pain threshold (mmHg) before the sample solution administration
C:cutoff presses (230mmHg)
(2) with the comparison of morphine
Circadian Std:ddY is that male mice (20-25g) experimentizes with stopping to take food.In this experiment, the tartrate of compound shown in (2) of employing table 1 uses Srm-Rhotaard as positive control as compound of the present invention.The tartrate of compound (2) dissolves with 0.9% normal saline solution, be modulated into the concentration of 5mg/2ml, 3mg/2ml and 1mg/2ml, Srm-Rhotaard dissolves with 0.9% normal saline solution, be modulated into the concentration of 5mg/2ml, 3mg/2ml and 1mg/2ml, as negative control, use 0.9% normal saline solution.Experiment is adopted and is pressed stimulating apparatus to carry out.Will be by before the test compound administration, with twice pain threshold of 30 minutes measuring spaces, selecting pain threshold for use is that the mouse of 50-100mmHg is used for experiment.With above-mentioned by the test compound solution respectively with the dosage intravenously administrable of 2ml/kg, after administration 10,20 and 30 minutes with pressing stimulating apparatus to measure pain threshold.Organize in contrast, with 0.9% same normal saline solution intravenous administration.The result the results are shown in the following table 8 with the inhibiting rate (%) shown in top (1) expression, by shown in the table 8 as can be seen, compound of the present invention has the analgesic activities with the morphine equality strength.
(3) with the experiment of morphine and usefulness
Circadian Std:ddY is that male mice (20-25g) experimentizes with stopping to take food.In this experiment, the tartrate of compound and Srm-Rhotaard are as compound of the present invention shown in (2) of employing table 1, the tartrate of compound (2) dissolves with 0.9% normal saline solution, be modulated into the concentration of 7mg/10ml, Srm-Rhotaard dissolves with 0.9% normal saline solution, is modulated into the concentration of 5mg/2ml, 3mg/2ml and 1mg/2ml.Contrast adopts 0.9% normal saline solution.Experiment is adopted and is pressed stimulating apparatus to carry out.
Will be by before the test compound administration, with twice pain threshold of 30 minutes measuring spaces, selecting pain threshold for use is that the mouse of 50-100mmHg is used for experiment.Mouse is divided into tartrate administration group, Srm-Rhotaard administration group, the tartrate that reaches compound (2) and the Srm-Rhotaard of control group, compound (2) and uses group.For the tartrate administration group of compound (2), with 0.9% normal saline solution solution of the tartrate of above-claimed cpd (2) dosage subcutaneous administration with 10ml/kg, after 30 minutes with the dosage intravenous administration of 0.9% normal saline solution solution with 2ml/kg; For morphine administration group, with the dosage subcutaneous administration of 0.9% normal saline solution with 10ml/kg, after 30 minutes with the normal saline solution solution of above-mentioned Srm-Rhotaard respectively with the dosage intravenous administration of 2ml/kg; Tartrate and morphine for compound (2) are also used group, with 0.9% normal saline solution solution of the tartrate of above-claimed cpd (2) dosage subcutaneous administration with 10ml/kg, after 30 minutes with the normal saline solution solution of above-mentioned Srm-Rhotaard respectively with the dosage intravenous administration of 2ml/kg; For control group,, with the dosage intravenously administrable of 0.9% normal saline solution, behind intravenously administrable, measured pain threshold in 10,20 and 30 minutes after 30 minutes with 2ml/kg with the dosage subcutaneous administration of 0.9% normal saline solution with 10ml/kg.
Result's inhibiting rate (%) expression of obtaining with top (1) same formula the results are shown in the table 9.By shown in the table 9 as can be seen, compound of the present invention can strengthen the analgesic activity of morphine consumingly.
(4) with the test of morphine antagonist and usefulness
Circadian Std:ddY is that male mice (20-25g) experimentizes with stopping to take food.In this experiment, the tartrate of compound (2) uses Srm-Rhotaard and anaesthetic antagonistic hydrochloric acid levallorphan in addition as compound of the present invention shown in the employing table 1.The tartrate of compound (2) dissolves with 0.9% normal saline solution, be modulated into the concentration of 10mg/2ml, Srm-Rhotaard dissolves with 0.9% normal saline solution, is modulated into the concentration of 10mg/2ml, the hydrochloric acid levallorphan dissolves with 0.9% normal saline solution, is modulated into the concentration of 1mg/10ml.Use 0.9% normal saline solution thing in contrast.Experiment is adopted and is pressed stimulating apparatus to carry out.
Before the administration of hydrochloric acid levallorphan, with twice pain threshold of 30 minutes measuring spaces, selecting pain threshold for use is that the mouse of 50-100mmHg is used for experiment.With the dosage subcutaneous administration of above-mentioned hydrochloric acid levallorphan solution with 10ml/kg, after 30 minutes with 0.9% normal saline solution solution of the tartrate of above-claimed cpd (2) or liquor morphinae hydrochloratis respectively with the dosage intravenously administrable of 2ml/kg, 10,20 and 30 minutes with pressing stimulating apparatus to measure pain threshold after this.In contrast, with 0.9% physiological saline with 10ml/kg dosage subcutaneous administration, after 30 minutes with the dosage intravenous administration of 0.9% normal saline solution with 2ml/kg.For individually dosed group of hydrochloric acid levallorphan, with the dosage subcutaneous administration of above-mentioned hydrochloric acid levallorphan solution with 10ml/kg, after 30 minutes with the dosage intravenous administration of 0.9% normal saline solution with 2ml/kg.
Result's inhibiting rate (%) expression of obtaining with top (1) same formula is listed in the table 10.By shown in the table 10 as can be seen, the analgesic activity of morphine is suppressed during simultaneously and with levallorphan, in contrast, the analgesic activity of compound of the present invention is not suppressed also with levallorphan the time.
Experimental example 2
Measure analgesic activities with hot plate method
Circadian Std:ddY is that male mice (20-25g) experimentizes with stopping to take food.Compound shown in the table 1 is made tartrate, be dissolved into the concentration of 10mg/10ml then respectively with 0.9% normal saline solution, as sample solution.Use 0.9% normal saline solution thing in contrast.In temperature is the columnar hot plate of 52 ℃ water bath internal fixing diameter 22cm, a high 11cm, put into mouse, its four limbs are contacted with hot plate, and the shock reaction (licking the action of forelimb) that shows during with contact is recorded to the time that this reaction occurs as the index of pain.In the sample solution administration preceding 1 hour,, the reaction times is excluded in outside the experiment the animal more than 25 seconds with the above-mentioned hot plate method assaying reaction time.In addition, for preventing to burn, the cutoff time is decided to be 50 seconds owing to heat causes the tissue of animal.The result represents with the inhibiting rate that following formula calculates.
Inhibiting rate (%)=(A-B) * 100/ (50-B)
A: the latent period after the sample solution administration (responselatency)
B: the latent period before the sample solution administration
The 50:cutoff time the results are shown in the following table 11.From shown in the table 11 as can be seen, compound of the present invention has the powerful pain-stopping activity, its action intensity than 14-O-to chlorobenzoyl aconine height.
Experimental example 3
Measure the antipyretic activity of the rat of yeast pyrogenicity
Circadian Wistar is that male rat (150-190g) experimentizes with stopping to take food.In the compound shown in the table 1, use compound (1) and compound (2), they are made tartrate, be dissolved into the concentration of 10mg/10ml then with 0.9% normal saline solution, as sample solution.Use 0.9% normal saline solution thing in contrast.Measure the rectal temperature of rat, then with 7.5% yeast/0.9% normal saline solution with the dosage of 1ml/100g body weight at the rat back subcutaneous administration, measure the rectal temperature of rat after 4 hours, select rise rat more than 1 ℃ of rectal temperature for use.The yeast administration after 5 hours with the sample solution subcutaneous administration.After the sample solution administration 2 hours, measure the rectal temperature of rat, the result represents with 2 hours the difference of rectal temperature before the yeast administration and after the sample solution administration.Provide the result in the table 12.As can be seen from Table 12, compound of the present invention has refrigeration function.
Experimental example 4
Measure anti-inflammatory activity with carrageenin (carrageenin) toes edema method
Circadian Std:ddY is that male mice (20-25g) experimentizes with stopping to take food.Compound shown in the table 1 is made tartrate, use the aseptic distillation water dissolution then, be modulated into the concentration of 30mg/10ml.Use sterile purified water thing in contrast.With the aqueous solution of said sample compound dosage oral administration with 10ml/kg, to be suspended in λ carrageenin (0.5mg/25 μ l) 25 μ l in 0.9% normal saline solution after 1 hour at the right hind toes subcutaneous administration of mouse, with 0.9% normal saline solution, 25 μ l at left hind toes subcutaneous administration.After the carrageenin administration 3 hours and 5 hours, measure the thickness of foot with dialgauge calliper slide calliper rule.Organize in contrast, with the dosage oral administration of sterile purified water with 10ml/kg, to be suspended in λ carrageenin (0.5mg/25 μ l) 25 μ l in 0.9% normal saline solution after 1 hour at the right hind toes subcutaneous administration of mouse, 0.9% normal saline solution, 25 μ l at left hind toes subcutaneous administration, are carried out equally with the occasion of above-mentioned experimental compound administration group.The result represents with the edema rate that following formula is calculated.
(R-L) * 100/L=edema rate (%)
R: the sufficient thickness of right hind
L: the sufficient thickness of left hind
The results are shown in the following table 13.As can be seen from Table 13, compound of the present invention has carrageenin toes edema restraining effect.
Experimental example 5 (acute toxicity)
Circadian Std:ddY is that male mice (20-25g) experimentizes with stopping to take food.The sample solution of test compound uses with experimental example 4 and prepares (30mg/10ml) with quadrat method.With the dosage oral administration of sample solution, observe 72 hours deadly quantity then with 10ml/kg.As a result, of the present invention no matter any compound is not all found dead example after with the dosage oral administration of 30mg/kg, proves that its toxicity is very low.Active (pressure stimulus method) the compound name inhibiting rate (*) of table 7 Town pain
(%) contrast 1 ± 314-O-is to chlorobenzoyl aconine 10 ± 4
(1) 48±12
(2) 43±10
(3) 36±10
(4) 29±8
(5) 40±10
(6) 27±11
(7) 35±10
(8) 26±7
(9) 31±12
(10) 23±7
(11) 25 ± 8*: mean value ± Standard Quasi table of error 8 and morphine De are Bi More compound name consumption inhibiting rate (%) (mean value ± Standard Quasi error)
(i.v., mg/kg) administration Hou De Time Inter (branch)
10 20 30 contrasts--2 ± 32 ± 50 ± 5 morphine 11 ± 22 ± 22 ± 1
3 13±7 18±10 12±8
5 38±12 30±10 29±12(2) 1 5±4 4±4 2±3
3 14±15 16±10 12±12
5 38 ± 13 27 ± 6 22 ± 7 tables 9
With the test morphine of morphine and usefulness and with compound (*) inhibiting rate (%, mean value ± Standard Quasi error) consumption (s.c. of consumption, morphine administration Hou De Time Inter (branch) (i.v., mg/kg) mg/kg) 10 20 30 contrast 0-4 ± 43 ± 42 ± 3
0 7 30±11 35±12 37±11
1 0 2±2 3±4 1±2
3 0 11±8 15±9 10±6
5 0 36±10 32±11 26±8
1 7 31±12 36±10 32±7
3 7 47±8 50±9 38±12
57 73 ± 13 77 ± 9 78 ± 9n=7. (*): the compound shown in the table 1 (2).The test of table 10 and morphine antagonist and usefulness
And with the consumption inhibiting rate (% of compound, mean value ± Standard Quasi error) levallorphan (mg/kg is i.v.) and with (a) (b) 10 20 30 of time (branch) consumption (mg/kg) behind the compound intravenous administration
0 0 0 -2±3 1±2 -3±3
1 0 0 3±4 -3±4 1±3
0 10 0 70±13 73±9 65±12
1 10 0 10±1(*) 10±7(*) 20±6(*)
0 0 10 85±15 80±20 65±21
10 10 86 ± 25 77 ± 14 67 ± 22 (a): morphine (b): the compound shown in the table 1 (2) (*): individually dosed group marked difference is arranged with morphine, P＜active (Hot plate method) compound name inhibiting rate (%, mean value ± Standard Quasi error) contrast 3 ± 514-O-of 0.01 table 11 Town pain is to chlorobenzoyl aconine 17 ± 7
(1) 52±12
(2) 76±11
(3) 39±11
(4) 35±9
(5) 37±10
(6) 46±8
(7) 49±11
(8) 48±8
(9) 46±7
(10) 40±10
(11) 34 ± 9 tables 12 are separated Hot effect compound amount (mg/kg, the s.c.) variation of rectal temperature (℃) contrast 0 1.9 ± 0.2
(1) 1 1.3±0.1
3 0.2±0.1
10 0.2±0.2
(2) 1 1.5±0.2
3 0.5±0.2
10 0.3 ± 0.1 table 13 anti-inflammatory activity compound name Fu Swollen leads (%, mean value ± Standard Quasi error)
3 hours 5 hours contrast 80 ± 10 92 ± 11
(d) 57±8 63±9
(1) 49±2 52±6
(2) 40±9 46±9
(3) 42±10 54±8
(4) 50±7 55±9
(5) 43±10 58±10
(6) 46±5 60±5
(7) 43±8 48±8
(8) 41±5 55±8
(9) 44±7 56±7
(10) 49±6 49±11
(11) 50 ± 5 52 ± 9 (d): 14-O-are 30mg/kg (per os) to the dosage of chlorobenzoyl aconine n=6. compound.
The clinical administration amount of analgesia of the present invention, anti-inflammatory agent, for the adult, the compound of above-mentioned (1) was advisable with 1-800mg/ day.Medicament of the present invention can use habitual formulation carrier or vehicle, make desirable formulation by conventional process clinical use is provided.In addition, for the effect that reaches medicine or for the ease of preparationization, compound of the present invention also can be made any needed salt and use.
Peroral administration tablet, pulvis, granule, capsule etc. also can contain habitual vehicle, for example lime carbonate, magnesiumcarbonate, calcium phosphate, W-Gum, yam starch, granulated sugar, lactose, talcum, Magnesium Stearate, Sudan Gum-arabic.Tablet can adopt the known method dressing.Peroral administration liquid preparation can be water-based or butyrous suspension, solution, syrup, elixir or other.
Preparation for injection, (1) compound shown in the formula can use with the form of salt, lysotype when preferably using, the auxiliary that can also contain suspension agent, stablizer and dispersion agent and so in addition also can contain sterile purified water, essential oil (for example Viscotrol C, Semen Maydis oil) or non-aqueous solvent, polyoxyethylene glycol, polypropylene glycol etc.
The preparation that is used for rectal administration is that the form with suppository composition provides, and can contain carrier well known in the art, for example polyoxyethylene glycol, lanolin, coconut wet goods.
The preparation that is used for topical provides with the form of ointment composition, plaster composition or poultice, can contain carrier well known in the art, for example Vaseline, paraffin, add water lanolin, whiteruss, kaolin, wilkinite, talcum, pure aluminium silicate, propylene glycol, sorbyl alcohol, hydrophilic Vaseline, polyoxyethylene glycol, wax, resin, refined wool fat, natural gum, glycerine, gelatin, polyacrylic acid, polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide etc.
Claims (2)
1. represented compound with aconitine type chemical constitution and the salt thereof of general formula (I)
In the formula
R
1Be hydrogen atom or hydroxyl,
R
2Be acetoxyl group,
R
3Be the alkyl of 1-4 carbon atom,
R
4Be
1. hydrogen atom, or
2. hydroxyl, or
3. acetoxyl group.
2. analgesic a, analgesia, anti-inflammatory agent is characterized in that, contain by aforesaid right requirement 1 by the represented compound or its salt of general formula (I) with aconitine type chemical constitution as effective constituent, and contain vehicle.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP47646/94 | 1994-02-09 | ||
| JP47646/1994 | 1994-02-09 | ||
| JP4764694 | 1994-02-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1123027A CN1123027A (en) | 1996-05-22 |
| CN1053184C true CN1053184C (en) | 2000-06-07 |
Family
ID=12781020
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95190076A Expired - Lifetime CN1053184C (en) | 1994-02-09 | 1995-02-09 | Novel aconitine-like compound and antipyretic analgesic anti-inflammatory agent |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US5770604A (en) |
| EP (1) | EP0693479B1 (en) |
| CN (1) | CN1053184C (en) |
| DE (1) | DE69512715T2 (en) |
| WO (1) | WO1995021827A1 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2983150B2 (en) | 1994-02-09 | 1999-11-29 | 三和生薬株式会社 | Novel aconitine-type compounds and analgesic / anti-inflammatory agents |
| US6896898B1 (en) * | 1999-11-19 | 2005-05-24 | Xel Herbaceuticals, Inc. | Transdermal delivery system for alkaloids of aconitum species |
| US20050042271A1 (en) * | 1999-11-19 | 2005-02-24 | Xel Herbaceuticals, Inc . | Transdermal delivery system for alkaloids of aconitum species |
| CN100443083C (en) * | 2005-03-25 | 2008-12-17 | 成都高新区智爽天然产物科技有限责任公司 | Use of aconine in medicine manufacture |
| CN101239947B (en) * | 2008-03-07 | 2010-12-08 | 中国科学院昆明植物研究所 | The preparation method of aconitine |
| US9085536B2 (en) | 2011-03-15 | 2015-07-21 | The Board Of Trustees Of The Leland Stanford Junior University | Aconitine compounds, compositions, uses, and preparation thereof |
| CN110092806B (en) * | 2018-01-30 | 2022-05-17 | 中国医学科学院药物研究所 | Analgesic C of aconite19Diterpene alkaloid glucoside and application thereof |
| CN111440112B (en) * | 2020-01-20 | 2022-11-25 | 成都中医药大学 | A kind of pyrolysis type diterpene alkaloid compound and its preparation method and application |
| CN113413383A (en) * | 2021-06-17 | 2021-09-21 | 广州中医药大学(广州中医药研究院) | Novel application of Songcuoling |
| CN116375645B (en) * | 2022-03-31 | 2025-04-01 | 好医生药业集团有限公司 | A class of eugenol ester derivatives and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03223255A (en) * | 1989-12-21 | 1991-10-02 | Sanwa Shiyouyaku Kk | Novel aconitine-based compound and analgesic and antiphlogistic agent |
| JPH0616553A (en) * | 1991-07-25 | 1994-01-25 | Sanwa Shiyouyaku Kk | Medicine useful for promoting blood circulation |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH085863B2 (en) * | 1987-02-27 | 1996-01-24 | 三和生薬株式会社 | 14-Anisoylaconine and novel analgesic / anti-inflammatory agent containing the same |
| JPH085862B2 (en) * | 1987-02-27 | 1996-01-24 | 三和生薬株式会社 | Novel aconitine compounds and analgesic / anti-inflammatory agents containing them as active ingredients |
| JPH085865B2 (en) * | 1987-04-06 | 1996-01-24 | 三和生薬株式会社 | Novel aconitine compounds and analgesic / anti-inflammatory agents containing them as active ingredients |
| JPH085866B2 (en) * | 1987-11-29 | 1996-01-24 | 三和生薬株式会社 | Novel aconitine compounds and analgesic / anti-inflammatory agents |
| JP3117251B2 (en) * | 1991-07-08 | 2000-12-11 | 三和生薬株式会社 | 14-Op-chlorobenzoyl aconine and analgesic / anti-inflammatory agent |
-
1995
- 1995-02-09 DE DE69512715T patent/DE69512715T2/en not_active Expired - Lifetime
- 1995-02-09 WO PCT/JP1995/000180 patent/WO1995021827A1/en not_active Ceased
- 1995-02-09 CN CN95190076A patent/CN1053184C/en not_active Expired - Lifetime
- 1995-02-09 US US08/530,189 patent/US5770604A/en not_active Expired - Lifetime
- 1995-02-09 EP EP95907864A patent/EP0693479B1/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03223255A (en) * | 1989-12-21 | 1991-10-02 | Sanwa Shiyouyaku Kk | Novel aconitine-based compound and analgesic and antiphlogistic agent |
| JPH0616553A (en) * | 1991-07-25 | 1994-01-25 | Sanwa Shiyouyaku Kk | Medicine useful for promoting blood circulation |
Also Published As
| Publication number | Publication date |
|---|---|
| US5770604A (en) | 1998-06-23 |
| EP0693479A4 (en) | 1995-12-04 |
| CN1123027A (en) | 1996-05-22 |
| DE69512715T2 (en) | 2000-03-02 |
| DE69512715D1 (en) | 1999-11-18 |
| WO1995021827A1 (en) | 1995-08-17 |
| EP0693479A1 (en) | 1996-01-24 |
| EP0693479B1 (en) | 1999-10-13 |
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Expiration termination date: 20150209 Granted publication date: 20000607 |